Corticotropin releasing factor antagonist, α-helical CRF9-41, reverses nicotine-induced conditioned, but not unconditioned, anxiety

Rationale: Unconditioned anxiogenic effects of nicotine have been observed in the social interaction (SI) test 5 min after injection of a low dose and both 5 min and 30 min after injection of a high dose. Conditioned anxiety has also been observed 24 h after testing in the SI with a high dose of nicotine. Objectives: In order to determine whether these three anxiogenic effects shared a common mechanism, we investigated the role of corticotropin releasing factor (CRF). We therefore examined whether the CRF antagonist alpha-helical CRF9-41 could block these three anxiogenic effects of nicotine. Methods: To test the unconditioned anxiogenic effects, pairs of male rats were tested in SI 5 min after s.c. vehicle or nicotine (0.1 mg/kg) or 30 min after s.c. vehicle or nicotine (0.45 mg/kg), and 30 min after i.c.v. artificial cerebrospinal fluid (aCSF) or alpha-helical CRF9-41. To test conditioned anxiety, rats were exposed to the SI test on day 1, 5 min after vehicle or nicotine (0.1 mg/kg). On day 2, they were re-tested in SI 30 min after i.c.v. aCSF or alpha-helical CRF9-41 (5 mug). Results: alpha-Helical CRF9-41 did not block the unconditioned anxiogenic effect of either dose of nicotine. Nicotine (0.1 mg/kg, 5 min) elicited a conditioned anxiogenic response that was significantly reversed by alpha-helical CRF9-41. The CRF antagonist alone had no effect. Conclusions: CRF is an important mediator of the conditioned anxiety to nicotine, but may not play a role in mediating the acute anxiogenic effects.